Transcriptome characterization of CHOPS syndrome, a novel genetic disorder caused by gain-of-function mutations of AFF4
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE64031 | GEO | 2015/01/27
SECONDARY ACCESSION(S): PRJNA269917
REPOSITORIES: GEO
Similar Datasets
Project description:AFF4 is a component of super elongation complex (SEC), which plays an important role in mobilizing paused RNA polymerase II at gene promoter regions. Using exome sequenging, we have identified a novel genetic disorder caused by missense mutations in AFF4. We propose CHOPS syndrome as a name for this new diagnosis. To evaluate the effect of identified missense mutations of AFF4, utilizing patient derived skin fibroblast cell lines, the gene expression analysis was perfomred. To characterize the transcriptome pattern observed in CHOPS syndrome, the skin fibroblast samples from two CHOPS syndrome probands and three healthy control subjects were used. Samples used for expression array include two CHOPs syndrome samples (CDL160: 6 year-old Caucasian female with 254S mut and CDL444: 12 year-old Caucasian male with 254A mut) and three age gender matched controls (GM01652: 11 year-old Caucasian female, GM02036 11 year-old Caucasian female and GM08398: 8 year-old Caucasian male).
2015-01-27 | E-GEOD-64031 | biostudies-arrayexpress
Project description:AFF4 was discovered as a scaffold protein of Super Elongation Complex (SEC) and exhibites an essential function on osteogenesis, tumorigenesis and odontogenesis. However, the adipogenic biological functions of AFF4 need further explorations. Here, we demonstrate that knockdown of AFF4 inhibits adipogenesis in both human mesenchymal stem cells (hMSCs) and lineage-committed 3T3-L1 preadipocytes. Conditional knocking down of Aff4 in transgenic mouse presents a thin body phenotype and impeded adipogenesis. Mechanistically, we define autophagy signaling as a crucial downstream of AFF4 through the combination of RNA-seq and ChIP-seq analyses. Depletion of AFF4 mediates the transcription of crutial autophagy genes ATG5 and ATG16L1. Simultaneous overexpression of ATG5 and ATG16L1 rescues the lineage commitment of AFF4-deficient cells. Our data elucidate that AFF4 is indispensable for adipogenic differentiation and reveal a novel mechanism for adipogenesis at transcriptional level.
2023-02-28 | GSE197354 | GEO
Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.
2023-07-02 | GSE207812 | GEO
Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.
2023-07-02 | GSE224754 | GEO
Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.
2023-07-02 | GSE224753 | GEO
Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.
2023-07-02 | GSE207810 | GEO
Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.
2023-07-02 | GSE207320 | GEO
Project description:P-TEFb, a heterodimer of kinase, CDK9, and Cyclin T1, is a critical regulator of promoter-proximal pause release of Pol II in metazoans. It is capable of forming three larger multiprotein complexes, including the super elongation complex (SEC), the BRD4/P-TEFb complex and the 7SK snRNP. In the SEC or the BRD4/P-TEFb, P-TEFb is enzymatically active, while in the 7SK snRNP, its activity is inhibited. The SEC consists of AFF1 or 4, ENL or AF9, ELL1, 2 or 3 and EAF1 or 2 in addition to P-TEFb, the only subunit with catalytic activity, and the noncatalytic subunits have been found to be able to regulate pause release through P-TEFb. One recent study showed that in human DLD-1 cells, the SEC only regulates pause release of heat shock (HS) genes, whereas the BRD4/P-TEFb complex regulates pause release of the rest of the genes. In this study, we found that AFF4 knockdown in human HEL cells decreased not only cellular level but also global chromatin occupancy of CTD serine 2 phosphorylated Pol II, and notably, increased promoter-proximal pause of Pol II on several hundred HS and thousands of non-HS genes. Mechanistically, AFF4 facilitates pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that the extent of impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.
2024-06-10 | GSE234619 | GEO
Project description:P-TEFb, a heterodimer of kinase, CDK9, and Cyclin T1, is a critical regulator of promoter-proximal pause release of Pol II in metazoans. It is capable of forming three larger multiprotein complexes, including the super elongation complex (SEC), the BRD4/P-TEFb complex and the 7SK snRNP. In the SEC or the BRD4/P-TEFb, P-TEFb is enzymatically active, while in the 7SK snRNP, its activity is inhibited. The SEC consists of AFF1 or 4, ENL or AF9, ELL1, 2 or 3 and EAF1 or 2 in addition to P-TEFb, the only subunit with catalytic activity, and the noncatalytic subunits have been found to be able to regulate pause release through P-TEFb. One recent study showed that in human DLD-1 cells, the SEC only regulates pause release of heat shock (HS) genes, whereas the BRD4/P-TEFb complex regulates pause release of the rest of the genes. In this study, we found that AFF4 knockdown in human HEL cells decreased not only cellular level but also global chromatin occupancy of CTD serine 2 phosphorylated Pol II, and notably, increased promoter-proximal pause of Pol II on several hundred HS and thousands of non-HS genes. Mechanistically, AFF4 facilitates pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that the extent of impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.
2024-06-10 | GSE234617 | GEO
Project description:P-TEFb, a heterodimer of kinase, CDK9, and Cyclin T1, is a critical regulator of promoter-proximal pause release of Pol II in metazoans. It is capable of forming three larger multiprotein complexes, including the super elongation complex (SEC), the BRD4/P-TEFb complex and the 7SK snRNP. In the SEC or the BRD4/P-TEFb, P-TEFb is enzymatically active, while in the 7SK snRNP, its activity is inhibited. The SEC consists of AFF1 or 4, ENL or AF9, ELL1, 2 or 3 and EAF1 or 2 in addition to P-TEFb, the only subunit with catalytic activity, and the noncatalytic subunits have been found to be able to regulate pause release through P-TEFb. One recent study showed that in human DLD-1 cells, the SEC only regulates pause release of heat shock (HS) genes, whereas the BRD4/P-TEFb complex regulates pause release of the rest of the genes. In this study, we found that AFF4 knockdown in human HEL cells decreased not only cellular level but also global chromatin occupancy of CTD serine 2 phosphorylated Pol II, and notably, increased promoter-proximal pause of Pol II on several hundred HS and thousands of non-HS genes. Mechanistically, AFF4 facilitates pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that the extent of impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.
2024-06-10 | GSE235444 | GEO